1. Field of the Invention
The invention relates generally to treatments of insulin resistance. More specifically, it relates to βarrestin2 protein and its roles in insulin sensitivity. The invention also relates to methods and reagents for diagnosing, preventing, and treating diseases or conditions associated with insulin resistance.
2. Background Art
Insulin resistance (or insulin insensitivity) has become one of the most serious public health threats in recent years. It leads to deregulation of glucose homeostasis and is associated with glucose intolerance, obesity, dyslipidemia, hypertension and cardiovascular disorder. As a compensatory response, body produces more insulin, leading to higher levels of blood insulin (hyperinsulinaemia). As the syndrome progresses, this eventually leads to diabetes.
Insulin resistance refers to a decreased capacity of circulating insulin to regulate glucose and lipid metabolism in adipose tissue, liver, and skeletal muscle, due to diminished insulin receptor (IR) response to insulin stimulation. Under normal conditions, insulin in circulation is recognized by IR on the cell surfaces of adipose tissue, liver, or skeletal muscle. After IR is stimulated by insulin, it phosphorylates insulin receptor substrate proteins (IRS proteins). Phosphorylation of IRS proteins in turn leads to the activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. The PI3K signaling pathway then mediates major metabolic actions of insulin.
Insulin signaling is a complex and highly regulated signaling networks. In the insulin signaling pathway, PI3K phosphorylates phosphatidylinositol-4,5-bisphosphate (PI4,5-P2) to produce phosphatidylinositol-3,4,5-trisphosphate (PI3,4,5-P3), which serves as a membrane anchor for Akt and PDKs (phosphoinositide-dependent protein kinases). Upon translocation to the membrane, Akt is phosphorylated by PDKs and becomes activated. Activated Akt in turn phosphorylates downstream kinases and transcription factors, thereby mediating most of the metabolic actions of insulin.
Defect at any critical nodes in the insulin signaling pathway (for example, defects in the activity of Ark) can result in insulin resistance. It has been shown that knockout of Akt (Cho, H. et al., “Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta),” Science, 292, 1728-31, 2001) or expression of Akt kinase-deficient mutants (Takata, M. et al., “Requirement for Akt (protein kinase B) in insulin-induced activation of glycogen synthase and phosphorylation of 4E-BP1 (PHAS-1),” J. Biol. Chem., 274, 20611-8, 1999) leads to insulin resistance. Even dysregulation of proteins that regulate Akt activity (such as, phosphatase-2A (PP2A) or tribbles-3 (TRB3)) can contribute to insulin resistance, demonstrating the pivotal role of Akt in insulin signaling. See, Resjo, S. et al., “Protein phosphatase 2A is the main phosphatase involved in the regulation of protein kinase B in rat adipocytes,” Cell Signal, 14, 231-8, 2002; and Du, K. et al., “TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver,” Science, 300, 1574-7, 2003.
Because insulin resistance usually develops before the occurrence of subsequent abnormalities (e.g., type II diabetes, glucose intolerance, obesity, dyslipidemia, hypertension, cardiovascular disorder, hyperuricemia, and hyperinsulinaemia), identifying biomarkers for insulin resistance would provide new approaches to preventing and/or treating insulin resistant patients.